Programmed cell death plays a critical role in regulating cell number and in eliminating stressed or damaged cells from normal tissues. Indeed, the network of apoptotic signalling mechanisms inherent in most cell types provides a major barrier to the development and progression of human cancer. Since most commonly used radiation and chemo-therapies rely on activation of apoptotic pathways to kill cancer cells, tumour cells which are capable of escaping programmed cell death often become resistant to treatment.
Apoptosis is generally mediated by a class of proteases known as Caspases. Once activated, Caspases cleave a number of cell death-related substrates, effecting destruction of the cell.
Tumour cells have devised a number of strategies to circumvent apoptosis. One recently reported molecular mechanism involves the overexpression of members of the IAP family. IAPs sabotage apoptosis by directly interacting with and neutralizing Caspases. One IAP, XIAP, has three functional domains referred to as BIR 1, 2 & 3 domains. BIR3 interacts directly with Caspase 9 and inhibits its ability to bind and cleave its natural substrate, Procaspase 3. Another prominent IAP is ML-IAP (also referred to as Livin), which comprises one BIR domain.
It has been reported that a proapoptotic mitochondrial protein, Smac (also known as DIABLO), is capable of neutralizing XIAP by binding to a peptide binding pocket (Smac binding site) on the surface of BIR3 thereby precluding interaction between XIAP and Caspase 9. Smac also interacts with the BIR domain of ML-IAP.
In the absence of IAP-Caspase 9 binding, apoptosis mediated through the action of Caspase 3/7 may be initiated.
WO2004/005248 (Novartis) describes XIAP inhibitor compounds. The compounds compete with Smac for binding to GST-BIR3 (see p. 21). In a model system using cells requiring XIAP for survival after TRAIL exposure these compounds overcome XIAP-dependent TRAIL resistance at concentrations in the range of 0.4 to 0.9 μM.
However, these compounds are only moderately efficient as evidenced by the moderate XIAP binding and their moderate ability to induce apoptosis and the growth of cancer cells in vivo.